Transcriptomic analysis reveals rescue of dysregulated genes in SBMA muscle upon silencing of AR co-factors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE193539 | GEO | 2022/11/04
REPOSITORIES: GEO
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Project description:To identify the gene expression changes that are specific to SBMA, we prepared total mRNA samples from the spinal cords of transgenic mice carrying a full-length human AR with 97 CAGs (AR-97Q), transgenic mice bearing a wild-type allele of AR with 24 CAGs (AR-24Q), and the wild-type littermates of the AR-97Q mice (C57BL/6). We used AR-97Q (Line #7-8) male mice because they show progressive muscular atrophy and weakness as well as SBMA-like pathology such as the accumulation of the pathogenic androgen receptor in the nucleus of motor neurons. Using microarray analysis, we identified the genes with significantly altered expression among the three types of mice.
2012-08-04 | GSE39865 | GEO
Project description:Emerging evidence implicates transcriptional dyseregulation within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disorder. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q KI), a polyQ AR transgenic model (AR97Q Tg), and a transgenic mouse which overexpresses wild type AR solely in muscle (HSA-AR Tg). We performed microarray analysis of lower hindlimb muscles taken from these three models using high density oligonucleotide arrays. Changes in gene expression relative to wild type controls were evaluated separately in each strain. We validated our results using quantitative RT-PCR. Patterns of gene expression that are common to all lines and unique to each are described. When considered globally, the degree of overlap between the three models is approximately equivalent, and several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, Huntingtonâ??s disease, muscle atrophy and myogenesis. By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA. Keywords: Gene expression in transgenic mice and disease state analysis We used microarray (38.5K oligo mouse array, which contain 35,302 of 70mer oligonucleotide probes largely derived from constitutively expressed exons and 3,482 of controls) to analyze gene expression in limb muscles of transgenic mice. Three mouse models of KD/SBMA were used: HSA-AR, AR113Q knock-in and AR97Q. HSA-AR transgenic male mice (n=5) and their WT brothers (n=8, all mice were 110-130 days of age) were used in this experiment. ARQ113-Knock In males (n=3, 3-4 months of age), and transgenic AR97Q males and WT brothers (n= 6 of each) were used in this study. For both HSA-AR and AR113Q samples, the log2 ratio of experimental samples (Cy5) and reference RNA(Cy3) was obtained, and log2 ratios from mutant samples were then subtracted from log2 ratios from WT controls. AR97Q males (Cy5) were simply compared with their WT brothers (Cy3) using a log2 ratio, rather than being first compared with reference RNA.
2010-10-12 | E-GEOD-10190 | biostudies-arrayexpress
Project description:To identify the gene expression changes that are specific to SBMA, we prepared total mRNA samples from the spinal cords of transgenic mice carrying a full-length human AR with 97 CAGs (AR-97Q), transgenic mice bearing a wild-type allele of AR with 24 CAGs (AR-24Q), and the wild-type littermates of the AR-97Q mice (C57BL/6). We used AR-97Q (Line #7-8) male mice because they show progressive muscular atrophy and weakness as well as SBMA-like pathology such as the accumulation of the pathogenic androgen receptor in the nucleus of motor neurons. Using microarray analysis, we identified the genes with significantly altered expression among the three types of mice. For each group, we examined the male mice at 7-9, 10-12, and 13-15 weeks of age. These stages were chosen because the AR-97Q mice are generally asymptomatic at 7-9 weeks of age (before-onset stage), present with mild motor impairment at 10-12 weeks (early stage), and are severely weakened with profound muscle atrophy at 13-15 weeks (advanced stage). RNA from the total spinal cord, excluding the dorsal root ganglia, was isolated from three mice of each genotype at each stage. For wild-type, pooled sample for three mice were used in each stage.
2012-08-03 | E-GEOD-39865 | biostudies-arrayexpress
Project description:To identify the gene expression changes by administering PG to SBMA model mice, we prepared total RNA samples from the spinal cords and skeletal muscles of transgenic mice carrying a full-length human AR with 97 CAGs (AR-97Q) that were treated with or without PG. We used AR-97Q (Line #7-8) male mice because they show progressive muscular atrophy and weakness as well as SBMA-like pathology such as the accumulation of the pathogenic androgen receptor in the nucleus of motor neurons. Using microarray analysis, we identified the genes with significantly altered expression of AR-97Q mice by PG treatment. For non-treated and PG-treated groups, we examined the male mice at 13 weeks of age. RNA from the total spinal cord and skeletal muscle was isolated from three mice of each group.
2013-10-29 | E-GEOD-51807 | biostudies-arrayexpress
Project description:To identify the gene expression changes by administering PG to SBMA model mice, we prepared total RNA samples from the spinal cords and skeletal muscles of transgenic mice carrying a full-length human AR with 97 CAGs (AR-97Q) that were treated with or without PG. We used AR-97Q (Line #7-8) male mice because they show progressive muscular atrophy and weakness as well as SBMA-like pathology such as the accumulation of the pathogenic androgen receptor in the nucleus of motor neurons. Using microarray analysis, we identified the genes with significantly altered expression of AR-97Q mice by PG treatment.
2013-10-29 | GSE51807 | GEO
Project description:Emerging evidence implicates transcriptional dyseregulation within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disorder. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q KI), a polyQ AR transgenic model (AR97Q Tg), and a transgenic mouse which overexpresses wild type AR solely in muscle (HSA-AR Tg). We performed microarray analysis of lower hindlimb muscles taken from these three models using high density oligonucleotide arrays. Changes in gene expression relative to wild type controls were evaluated separately in each strain. We validated our results using quantitative RT-PCR. Patterns of gene expression that are common to all lines and unique to each are described. When considered globally, the degree of overlap between the three models is approximately equivalent, and several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, Huntington’s disease, muscle atrophy and myogenesis. By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA. Keywords: Gene expression in transgenic mice and disease state analysis
2010-10-12 | GSE10190 | GEO
Project description:Kennedy’s disease/Spinobulbar muscular atrophy (KD/SBMA) is a degenerative neuromuscular disease affecting males. This disease is caused by polyglutamine expansion mutations of the androgen receptor (AR) gene. Although KD/SBMA has been traditionally considered a motor neuron disease, emerging evidence points to a central etiological role of muscle. We previously reported a microarray study of genes regulated in muscle of three genetically unique mouse models of KD/SBMA but were unable to those which are androgen-dependent or are associated with onset of symptoms. Methodology/principal findings: In the current study we examined the time course and androgen-dependence of transcriptional changes in the HSA-AR transgenic (Tg) mouse model, in which females have a severe phenotype after acute testosterone treatment. Using microarray analysis we identified regulated genes at the onset and peak of muscle weakness in testosterone-treated Tg females. We found both transient and persistent groups of regulated genes and analysis of gene function indicated functional groups such as mitochondrion, ion and nucleotide binding, muscle development, and sarcomere maintenance. By comparing the current results with those from the three previously reported models we were able to identify KD/SBMA candidate genes that are androgen dependent, and occur early in the disease process, properties which are promising for targeted therapeutics.
2015-03-22 | GSE61886 | GEO
Project description:The pattern of gene expression changes was analyzed in the skeletal muscle of transgenic mouse models of Spinal and bulbar muscular atrophy (SBMA) at 1 and 2 month of age.
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Project description:The aim of this study is to understand the mechanisms of TDP-43 neurotoxicity. Here, we perform a RNA-Seq analysis in TDP-43 gain-of-fucntion (GOF) , TDP-43 loss-of-function and wild-type late pupae heads (73-90 hours APF) and perform TDP-43 GOF vs wild type and TDP-43 LOF vs wild-type differential expression analysis to show that both mechanisms presents defects in ecdysone receptor (ECR)-dependeint transcriptional program switching, and strongly deregulate expression from the neuronal microtubule associated protien Map205. RNA-seq was performed in two wild-type D.melanogaster biological replicates (Canton S, w1118 ), four biological replicates for TDP-43 (LOF) with two distinct genotypes (dTDP-43Δ142/Df(2R)106,dTDP-43Δ23/Δ142 ) and two TDP-43 GOF biological replicates (act5c>dTDP-43 ).
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